Submissions for variant NM_014141.6(CNTNAP2):c.2123T>C (p.Val708Ala)

gnomAD frequency: 0.00151  dbSNP: rs148453565

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766798	SCV000240779	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing	Observed as a rare heterozygous missense variant in a population of individuals with autism spectrum disorder; however, the authors found no significant association with autism risk (Murdoch et al., 2015); This variant is associated with the following publications: (PMID: 25621974)
Genetic Services Laboratory, University of Chicago	RCV000187199	SCV000247056	uncertain significance	not specified	2014-10-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000187199	SCV000336099	likely benign	not specified	2015-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085121	SCV000563245	likely benign	Cortical dysplasia-focal epilepsy syndrome	2025-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515254	SCV000611462	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317086	SCV000850592	likely benign	Inborn genetic diseases	2021-11-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515254	SCV002496059	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2021-05-16	criteria provided, single submitter	clinical testing	CNTNAP2 NM_014141.5 exon 14 p.Val708Ala (c.2123T>C): This variant has not been reported in the literature but is present in 0.4% (200/41378) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-147903589-T-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:205256). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766798	SCV002540912	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000187199	SCV004813039	uncertain significance	not specified	2024-02-14	criteria provided, single submitter	clinical testing	Variant summary: CNTNAP2 c.2123T>C (p.Val708Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 250820 control chromosomes. c.2123T>C has been reported in the literature in at-least one individual affected with Autism, however insufficient information was provided for further analysis (example, Murdoch_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Autism, Susceptibility To, 15. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25621974). ClinVar contains an entry for this variant (Variation ID: 205256). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003967470	SCV004785451	likely benign	CNTNAP2-related disorder	2019-08-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).